US3446789A - Analogues of cyclic peptides containing disulfide bonds without disulfide bonds - Google Patents

Analogues of cyclic peptides containing disulfide bonds without disulfide bonds Download PDF

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Publication number
US3446789A
US3446789A US476162A US3446789DA US3446789A US 3446789 A US3446789 A US 3446789A US 476162 A US476162 A US 476162A US 3446789D A US3446789D A US 3446789DA US 3446789 A US3446789 A US 3446789A
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Prior art keywords
disulfide bonds
analogues
solution
cyclic peptides
alpha
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Expired - Lifetime
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US476162A
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English (en)
Inventor
Josef Rudinger
Karel Jost
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Czech Academy of Sciences CAS
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Czech Academy of Sciences CAS
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/16—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/15—Oxytocin or vasopressin; related peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/26—Containing cys-cys disulfide bridge between nonadjacent cysteine residues
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/27—Cyclic peptide or cyclic protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/32—Modification to prevent enzymatic degradation

Definitions

  • This invention concerns cyclic peptide derivatives and analogues of natural hormones of the oxytocin, Vasopressin and insulin type and a method of making these compounds.
  • These compounds of the invention have the general formula RLCHC O-A-B-C-D-NH. CH. C 0.13.
  • A, B, C, D are L-alpha-amino acid residues
  • R is H or NH or a substituted NH; group, the substituent being a protective group such as benzyloxycarboxyl, tertiary butyloxycarbonyl, o-nitrophenylsulfenyl, tosyl, formyl, etc., or an L-alpha-amino acid residue or a peptide chain containing 2 to 6 L-alpha-amino acids, or a residue of L-alpha-amino acids substituted by a protective group as indicated before and wherein R is OH or NH or NH substituted by an L-alpha-amino acid residue or peptide chain, which latter may include a protective group as indicated and wherein X is CH S, CH CH CH NH, CH O, NHNH or CONH.
  • the prior art substances generally are of the type where A, B, C, D have the same significance as above R is H or an amino acid or a peptide residue attached through the carboxyl end, and R is a peptide chain attached through the amino end.
  • R is H or an amino acid or a peptide residue attached through the carboxyl end, and R is a peptide chain attached through the amino end.
  • hormones such as oxytocin, Vasopressin, vasotocin, isotocin and insulin.
  • These hormones whether isolated from natural sources or prepared synthetically (oxytocin, vasopressins) are in broad pharmacological use.
  • Such use has also been made of some of the synthetic analogues of these hormones derived from the structure of the natural hormones by substituting functional groups, such as substitution of certain amino acid residues by other groups.
  • the disulfide group per se is relatively unstable both chemically (Rossler, 0., Science, 128, 1281 (1958), and metabolically (Rychlik, I., Oxytocin, Vasopressin and the Structural Analogues, Proc. Second Internat Pharmacol. Meeting, Pergamon Press, 1964, pp. 153-162; Tomizava, R. R., J. Biol. Chem., 237, 3393 (1962), and reaction at this site is the main reason for loss of activity of these hormones. The same applies to all known synthetic analogues with biological activity.
  • the present invention therefore is directed to cyclic compounds and their formation from non-cyclical peptides or their derivatives which cyclic compounds contain as the group designated X in the above formula one of the following groups: CH S, CH CH CH NH, CH O, NHNH or CONH.
  • the compounds prepared, e.g., by the procedure described below, have a biological activity similar to that of the peptides with a disulfide bridge.
  • EXAMPLE 3 The amide of tyrosyl-isoleucyl-glutaminyl-asp araginyl- S- 3 -c ar-b oxypropyl -cysteinyl-prolyl-leucylglycine 1.71 gr. of benzyloxycarbonyl-oetapeptide amide were dissolved in liquid ammonia (150 ml. distilled over Na) and sodium was added in small pieces until a deep purple color lasted 8 min.
  • This unpurified ester was dissolved in .trifiuoracetic acid ml) and after 2 hrs. at room temperature the reaction mixture was evaporated in vacuum.
  • the dry powder was dissolved in 10% ethyl alcohol and filtered through a column of sulfonate ion exchanger (Zerolite 225 in the H+ cycle). The column was washed with water to a neutral pH and the product was eluted with 10% pyridine. T he later eluate was then concentrated to a small volume and lyophilized, and the resulting product was chromatographed on a column of Dowex 1 x 2 (200-400 mesh, pyridine-acetate cycle) using gradient elution (1% pyridine-2% acetic acid).
  • the product was electrophoretically and chromatographically homogeneous.
  • reaction mixture was dililited with 8 ml. dimethylformamide and 5.85 mg. of N- ethylpiperidine were added. After 9 days of mixing at room temperature the reaction mixture was dried, and the powder disolved in 5 ml. water and filtered gradually through a column of Dowex 50, Amberlit IR-4B and Zerolit 225. The eluate was concentrated and lyophylized, yielding 16.6 mg. of product, homogeneous electttrophoretically and chromatograph-ically (negative ninhydrin reaction, positive Pauly and iodopla-tinate reactions) contairiing of peptide material on N analysis.
  • Amino acid analysis Asp 1.10, Cys [(CH COOM] 0.70, Glu 0.90, Gly 1.00, Ile 0.95, Leu 1.04, Pro 1.00, Tyr 0.70.
  • Biological activity oxytocic activity on the rat uterus in vi-tro 60 units/mg; vasodepressor activity: 25 units/mg, antiduretic activity in intact alcohol-treated rats-1 unit/mg.
  • EXAMPLE 5 The ter-t. butyl-ester of alpha-tosylamino-gammachlorobutyric acid To a solution of alpha-tosyl-L-alpha, gamma-diaminobutyric acid (5.5 mg.) in azeotropic HCl (100 ml.), warmed to 80 C. we added sodium nitrite (40 gr.) over a period of 5 min. The reaction mixture was allowed to cool to room temperature and was shaken up with ether and the ether layer was washed with 5% perchloric acid and water, and dried with sodium sulfate, the ether being extracted in vacuo. The residue was dissolved in 100 ml.
  • N-tosyl-carba -oxytocin N benzyloxycarbonyl-S-benzyl-octapeptide-amide was reduced by Na in liquid ammonia and alkylated in situ with tertiary butyl ester of alpha-tosylamino-gammaiodobutyric acid as in the case of deamino-carba-oxytocin.
  • the unpurified product was hydrolyzed with trifiuoracetic acid, and the latter was removed with Ze'rolite 225.
  • the product was purified on a column of Dowex 1 X 2 using gradient elution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US476162A 1964-07-27 1965-07-30 Analogues of cyclic peptides containing disulfide bonds without disulfide bonds Expired - Lifetime US3446789A (en)

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Application Number Priority Date Filing Date Title
CS432464 1964-07-27
US47616265A 1965-07-30 1965-07-30

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US3446789A true US3446789A (en) 1969-05-27

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NL (1) NL6509712A (enrdf_load_stackoverflow)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3875136A (en) * 1971-07-07 1975-04-01 Ciba Geigy Corp Process for the manufacture of peptides containing cystine
US3896105A (en) * 1974-04-01 1975-07-22 American Home Prod (n-propionyl) -gly-cys-lys-asn-phe-phe-trp-lys-thr-phe-thr-ser-cys-oh and intermediates
US3956260A (en) * 1967-11-09 1976-05-11 Ciba-Geigy Corporation Hypocalcaemic peptides and processes for their manufacture
FR2320109A1 (fr) * 1975-08-08 1977-03-04 Merck & Co Inc Analogues de somatostatine
EP0002264A1 (en) * 1977-12-01 1979-06-13 Merck & Co. Inc. Somatostatin analogs, process for their preparation and pharmaceutical composition thereof
US4482486A (en) * 1982-04-20 1984-11-13 Ceskoslovenska Akademie Ved Analogs of vasopressin
WO1993001206A1 (en) * 1991-06-14 1993-01-21 New York University Conformationally restricted biologically active peptides, methods for their production and uses thereof
US6028168A (en) * 1991-08-09 2000-02-22 Winfried Kolbeck Lanthionine bridged peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3956260A (en) * 1967-11-09 1976-05-11 Ciba-Geigy Corporation Hypocalcaemic peptides and processes for their manufacture
US3875136A (en) * 1971-07-07 1975-04-01 Ciba Geigy Corp Process for the manufacture of peptides containing cystine
US3896105A (en) * 1974-04-01 1975-07-22 American Home Prod (n-propionyl) -gly-cys-lys-asn-phe-phe-trp-lys-thr-phe-thr-ser-cys-oh and intermediates
FR2320109A1 (fr) * 1975-08-08 1977-03-04 Merck & Co Inc Analogues de somatostatine
EP0002264A1 (en) * 1977-12-01 1979-06-13 Merck & Co. Inc. Somatostatin analogs, process for their preparation and pharmaceutical composition thereof
US4482486A (en) * 1982-04-20 1984-11-13 Ceskoslovenska Akademie Ved Analogs of vasopressin
WO1993001206A1 (en) * 1991-06-14 1993-01-21 New York University Conformationally restricted biologically active peptides, methods for their production and uses thereof
US5364851A (en) * 1991-06-14 1994-11-15 International Synthecon, Llc Conformationally restricted biologically active peptides, methods for their production and uses thereof
US6028168A (en) * 1991-08-09 2000-02-22 Winfried Kolbeck Lanthionine bridged peptides
US6268339B1 (en) 1991-08-09 2001-07-31 Winfried Kolbeck Lanthionine bridged peptides
US6673769B2 (en) 1991-08-09 2004-01-06 Winfried Kolbeck Lanthionine bridged peptides

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NL6509712A (enrdf_load_stackoverflow) 1966-01-28

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